Many diketopiperazines of the general formula (1) are known to possess pharmacological and other biological activities, and libraries of such compounds have been synthesized to identify other diketopiperazines having beneficial biological and medicinal activities. See, e,g., Smith et al., Bioorg. Med. Chem Letters, 8:2369-2374 (1998); Nitecki et al., J. Org. Chem., 33:864-866 (1968); U.S. Pat. No. 5,817,751; and PCT application WO 96/00391. Diketopiperazines of formula (1) have been synthesized by a variety of methods, but, a thermal cyclization of the corresponding dipeptide to produce the cyclic product seems to be the method of choice because of its simplicity. In addition, the method is known to produce sterically-pure product (Nitecki et al., J. Org. Chem., 33:864-866 (1968)).
However, several groups of workers have encountered difficulty in employing the thermal cyclization method to synthesize diketopiperazines containing an aspartic acid residue. The inability of the dipeptide to form a cyclic product has been attributed to the presence of the free β carboxyl group of the aspartic acid. Similar difficulties would be expected synthesizing diketopiperazines containing a glutamic acid. Consequently, a new strategy to synthesize diketopiperazines wherein one of the amino acid is aspartic acid or glutamic acid is needed.